Abstract Lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Here, a viscous cycle of infection and inflammation lead to persistent neutrophilia and bronchiectasis that destroy the lung. One of the cornerstones of a comprehensive treatment plan is the use of anti-inflammatory drugs. While the significance of anti-inflammatory treatments was realized in the 1990s, there remains a dearth of drug therapies aimed toward treating the powerful and relentless inflammation in CF patients. Corticosteroids, used during pulmonary exacerbations, have positive effects and improve CF pathophysiology, such as reducing mucus and edema, inhibiting chemotaxis and adhesion, and activating leukocytes. Corticosteroids are not effective for long-term use due to their extensive side-effects. Nonetheless, anti-inflammatories remain an attractive option for the treatment of CF lung disease. Orai1 is a plasma membrane Ca2+ channel that is expressed in the lung and plays in key role in mediating inflammation. For example, activation of Orai1 occurs during store operated Ca2+ entry (SOCE), which in airway epithelia triggers secretion of the neutrophil chemoattractant IL-8. Therefore, inhibition of Orai1 is an attractive, drugable target. Yet to date, no anti-Orai1 therapies exist. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is a secreted protein that is highly expressed in the lung and is thought to play a critical role in maintaining lung health. SPLUNC1 is abundant in broncho-alveolar lavage, suggesting that it plays a role in the innate defense of the lower airways. Importantly, we have recently discovered that SPLUNC1 negatively regulates Orai1. Thus, our data indicate that SPLUNC1 inhibits store operated Ca2+ entry (SOCE) and has the potential to reduce CF inflammation. Indeed, SPLUNC1 knockout mice have a hyperinflammatory lung phenotype and SPLUNC1 protein is absent from CF patient?s BAL. We have identified the active site within SPLUNC1 that regulates Orai1, and a peptide corresponding to this region (called ?6) inhibits Orai1 in an equipotent fashion as full length SPLUNC1 and is anti-inflammatory in an allergic mouse model. In this study, we propose to develop novel ?6 peptide analogues that reduce inflammation by inhibiting Orai1-dependent Ca2+ influx and to test them in murine chronic CF infection models. There are no current effective anti-inflammatories for CF, so this constitutes a novel approach. In addition, this is the first therapeutic that targets Orai1. Furthermore, several inflammatory cells will be tested for inflammation control using ?6 and its mutants.